PROJECT SUMMARY Our laboratory and others have utilized in vitro and in vivo approaches to define potential vulnerabilities in peripheral T-cell lymphomas (PTCLs) that can be targeted with small molecules or other approaches. Here we will focus on the induction of apoptosis through informed combinations. In preliminary data, we show that ALRN- 6924, a stapled peptide that activates wild-type p53 by inhibiting interactions with both MDM2 and MDMX, is broadly active in PTCL cell lines, in vivo models and patients. Second, we show that small molecule mimetics of the anti-apoptotic BH3 proteins BCL2, BCL-xL and MCL1 can be selectively utilized to target PTCLs in vitro and in vivo based on a functional assessment of BH3 protein dependence called BH3 profiling. This technique quantifies the extent of ?apoptotic priming? induced by specific proapoptotic peptides, which provides a functional readout of the cell's addiction to individual antiapoptotic BH3 proteins like BCL2. Third, we have established and extensively characterized a panel of in vitro and in vivo models of PTCL. Among these are >30 patient-derived xenografts (PDXs) across 10 different PTCL subtypes and transgenic mice with compartment-specific expression of PTCL-associated transgenes. Fourth, we have used PDX models to perform phase II-like pre- clinical trials of MDM2 inhibition, to generate predictive biomarkers, and to define mechanisms of acquired in vivo resistance with PDXs that relapse during in vivo drug treatment. Finally, we demonstrate that chimeric antigen receptor T cells directed against the tetraspanin CD37 (CART37) can eradicate PTCL cells in vitro and in vivo. Strikingly, CART37 cells do not cause fratricide, kill human myeloid cells or target non-malignant T cells. Our central goal is to develop informed strategies that improve outcomes for patients with PTCL. There are promising new approaches outlined in Projects 1 and 2 that block essential signaling or target epigenetic defects. We will collaborate closely with these Projects to define synergies and antagonisms within well-characterized model systems and primary samples (from Core B). Models with acquired in vivo resistance will be interrogated to identify biomarkers (developed with Core C) that predict sensitivity and therapeutic approaches that overcome the resistance. Aim 1 is to define the effects from combining chimeric antigen receptor T cells directed against CD37 with agents that induce apoptosis in PTCL (with Markus Mschen/John Chan, Project 1). Aim 2 is to define combinations that target PTCL-specific alterations and apoptosis (with Markus Mschen/John Chan, Project 1 and Sandeep Dave, Project 2). The data from this Project will be used to select the most promising combinations that induce PTCL cell apoptosis and eradication. Through our existing clinical trials network (Core B), we will rapidly translate these combinations into biomarker-driven, human studies for patients with PTCL.